We seek to acquire a 12 Tesla FTMS system with electron-capture dissociation (ECD) to apply top-down proteomics strategies to a variety of important projects relevant to human health. To augment the instrumentation, we propose to implement electron-transfer dissociation (ETD) and a compensated ICR trap to realize a unique high-end instrument. The projects to which the instrument will be applied represent a balance between translational (disease-related) and fundamental (basic) research. The disease-related research projects have impact in the understanding and treatment of arthritis, autoimmunity, cancer, diabetes, HIV, and blood disorders. The basic science projects seek an understanding of basic life processes related to anesthesiology, cellular signaling, energy transfer, and protein function, binding, and interaction. Each project requires top-down protein sequencing to solve ensemble problems of protein post-translational modification or to address important problems in the biochemistry and biophysics of protein interactions and structural change. These problems are not soluble by bottom-up methods. The use of high-field magnet-based spectrometers is a major challenge today. Nevertheless, the research enabled by this unique instrument will direct strategies to expand the role of mass spectrometry for tomorrow's research in probing intact proteins and answering systems biological questions. PUBLIC HEALTH RELEVANCE We are proposing a unique mass spectrometer system that will provide unparalleled capabilities to understand a broad array of diseases including arthritis, autoimmunity, diabetes, HIV, blood disorders, anesthesiology and general biological processes. It will also support basic research aimed at the fundamentals of protein modification and interaction. As we develop the instruments capabilities, we expect to find opportunities to improve human health by solving problems that were previously intractable. [unreadable] [unreadable] [unreadable]